Affective and mood disorders are included in a group of mental disorders characterized by neuroendocrine dysregulation and are characterized by a disturbance in the regulation of mood, behavior, and affect. Affective and mood disorders can have serious impact on an individual's functional ability, interpersonal relationships and behavior. Major depression and dysthymia are examples such disorders.
Major depression is a syndromal, episodic and recurrent illness with both psychological and biological components. A diagnosis of bipolar disorder is given to those patients with recurring depression and mania. Those patients with recurrent depression alone have a unipolar pattern. Within the spectrum of depressive illness, there are two distinct subtypes: melancholic depression and atypical depression (Gold et al., N. Engl. J. Med., 319:348-353 (1988); and Gold et al., N. Engl. J. Med., 319:413-420 (1988)).
Melancholic depression is equally common among those with a pattern of unipolar and bipolar depression. Melancholic depression is characterized by hyposomnia (early morning awakening), anorexia and diurnal variation in mood, and is associated with a state of hyperarousal in which patients are painfully preoccupied with personal inadequacy, loss, feelings of worthlessness, guilt and suicidal ideation (Licinio et al., Bailliere's Clin. Endocrin. Met., 5(1):51-58 (1991)).
Atypical depression is more common in bipolar patients than in unipolar depressed patients. Atypical depression is characterized by a state which seems to be opposite to that of melancholic depression. Patients with atypical depression have a syndrome of hypoarousal with hypersomnia, hyperphagia, weight gain and mood liability (Licinio et al., Bailliere's Clin. Endocrin. Met., 5 (1):51-58 (1991)).
Neuroendocrine dysregulation, specifically changes in the hypothalamic-pituitary-adrenal (HPA) axis, has been investigated as a biological correlate of depression. Overall, the HPA axis regulates physiologic responses to stress. The hypothalamus controls endocrine functions and the autonomic nervous system. It is involved in behaviors related to fight, flight, feeding and mating, many of which are altered during episodes of depression. The hypothalamus releases corticotrophic-releasing hormone (CRH) in response to stress, which then stimulates the anterior pituitary to secrete adrenocorticotrophic-releasing hormone (ACTH). ACTH prompts the adrenal cortex to release cortisol which, through elaborate feedback mechanisms signals the hypothalamus to increase or decrease CRH production.
Under ordinary circumstances, activation of hypothalamic CRH is terminated rapidly by the negative feedback of rising glucocorticoid levels. However, in melancholic depression, hypercortisolism does not adequately restrain the production of CRH in the hypothalamus. Thus, in melancholic depression, CRH levels are chronically elevated causing hyperactivity of the HPA axis, hypercortisolism and ACTH levels that are numerically normal, but excessive in the context of high levels of circulating cortisol (Gold et al., N. Engl. J. Med., 314:1329-1335 (1986)). Antidepressant treatments consistently lower HPA axis activity in individuals with melancholic depression. In contrast, atypical depression is associated with hyposecretion of hypothalamic CRH. Thus, in atypical depression, hypothalamic CRH levels are lower than normal causing hypoactivity of the HPA axis. For a review, see Gold et al., Mol. Psychiatry, 1:257-264 (1996).
Dysthymia is a chronic disorder characterized by symptoms that include poor appetite or overeating, low energy (decreased arousal), insomnia or hypersomnia, and poor concentration. These functions are modulated by neuropeptides in the brain, such as CRH (Vale, W. et al., Science, 213:1394-1397 (1981)). Generally, dysthymia is characterized by hypothalamic CRH levels that are higher than normal, thereby causing hyperactivity of the HPA axis. However, in dysthymia, hypothalamic CRH levels can be lower than normal, causing hypoactivity of the HPA axis, in individuals with a higher than normal body mass index (BMI). Thus, in dysthymia, hypothalamic CRH levels are inversely related to the BMI of the individual.
Effective disorders are extremely common in general medical practice, as well as in psychiatry. The severity of these conditions covers an extraordinarily broad range, from normal grief reactions to severe, incapacitating, and sometimes fatal psychosis. The lifetime risk of suicide in major affective disorders is about 10 to 15%, but this statistic does not begin to represent the morbidity and cost of this group of under-diagnosed illnesses. Typically these disorders are treated with antidepressant agents or lithium salts (GOODMAN AND GILMAN'S THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, Eight Ed., 1990; Pergramon Press, New York, N.Y.). Nevertheless, many shortcomings and problems continue to be associated with all drugs used to treat affective disorders. In addition to less than-dramatic efficacy in some cases, virtually all the drugs used to treat disorders of mood are potentially lethal when acute over dosage occurs and can cause appreciable morbidity even with careful clinical use.